Mycosis Fungoides With Large Cell Lymphoma Transformation: A Report of a Rare Case

Introduction

Mycosis fungoides is the most common cutaneous T-cell lymphoma [1], accounting for nearly 50% of primary cutaneous lymphomas [2]. It has several variants, including folliculotropic mycosis fungoides, pagetoid reticulosis, and granulomatous cutis laxa [3]. Interstitial mycosis fungoides is a rare variant that is classified under granulomatous mycosis fungoides [4]. Although systemic lymphoma can secondarily involve the skin and may show a histological pattern similar to that of primary cutaneous T-cell lymphoma, treatment differs substantially and is addressed separately. Primary cutaneous lymphomas, which are a type of extranodal non-Hodgkin lymphoma, are divided into cutaneous B-cell lymphomas and cutaneous T-cell lymphomas, which include, among others, mycosis fungoides and its variants [2].

Mycosis fungoides, the classic Alibert-Bazin form, consists of a monoclonal epidermal proliferation of mature T lymphocytes with cerebriform nuclei and is generally cluster of differentiation (CD) 4–positive [1–3]. It is suggested that the cause of this T cell proliferation is an inflammatory process [4]. The disease progresses insidiously over years, with erythematous, pruritic, and scaly patches [4], which evolve into infiltrated plaques and, later, tumors [2]. The skin lesions demonstrate a tropism for covered areas [2] but can appear anywhere on the body [4]. The appearance of tumors not preceded by patches and plaques strongly suggests against the diagnosis of mycosis fungoides [2]. However, in the more advanced stages of the disease, such as large cell lymphoma transformation, there can be visceral and lymph node involvement [2].

Epidemiological data show that the population most affected by mycosis fungoides is men between 55 and 60 years of age [5]; however, it can also affect children and adolescents [2,6]. The annual incidence of mycosis fungoides is estimated to be 1 in 100 000 [2].

The prognosis depends on several factors, such as the stage of the disease at which the diagnosis occurs, the type and extent of the skin lesions, and the presence or absence of involvement of other organs. Thus, the diagnosis of mycosis fungoides tends to be challenging, due to the polymorphism of the dermatological lesions that manifest in the disease and the variety of histopathological findings that can be present [7].

Folliculotropic mycosis fungoides is defined by the presence of folliculotropic infiltrates, with tropism for the head and neck regions. On examination, papules, acneic lesions, plaques, or tumors are present. Compared with in other forms of the disease, pruritus in folliculotropic mycosis fungoides is more intense and can serve as a marker of disease progression. Severe pruritus predisposes patients to secondary bacterial infections of the lesions, further worsening the clinical course. Like other types of mycosis fungoides, the folliculotropic variant is more common in adult men. However, the survival rate is lower, ranging from 70% to 80% at 5 years [2].

Transformation into large cell lymphoma occurs when neoplastic cells undergo histopathological and molecular changes that lead to their growth. It can be considered to occur when there are more than 25% of large cells in the microscopic analysis or in the presence of aggregates of large cells [8]. This phenomenon can occur in 20% to 55% of advanced cases [8]. The transformation of mycosis fungoides into large cell lymphoma is associated with a poor prognosis and a 5-year survival rate of less than 20% [8], representing a more aggressive disease course than that of classic mycosis fungoides.

This case report has some limitations, as parts of the phototherapy and chemotherapy were performed at another university hospital. Additionally, the patient did not attend consultations regularly, resulting in significant time gaps between visits. Routine examinations were generally unremarkable, with clinically significant details appearing more often during non-routine appointments.

The objective of this study is to report a rare and fatal case of transformation of mycosis fungoides into large cell lymphoma at a quaternary university hospital.

Case Report

A 20-year-old male patient, with no previous comorbidities, sought medical attention in the dermatology department of a quaternary university hospital in July 2007. He presented with dermatological lesions of varying appearance in the chest, right arm, and right thigh regions. He reported that his brother had similar lesions in the axillary region, primarily presenting with pruritus.

A biopsy was requested by the initial physician, which revealed epidermotropic T-cell lymphoma. Immunohistochemistry showed CD3 positivity in 100% of epidermal and dermal cells; CD8 positivity in 5% of epidermal cells and 10% to 20% of dermal cells; CD5 positivity in 20% of epidermal cells and 10% of dermal cells; CD7 positivity in 20% of epidermal cells and 50% of dermal cells; and CD20 negativity in both the epidermis and dermis. Furthermore, the biopsy showed lichenoid infiltrate, mainly represented by atypical lymphocytes with epidermotropism and the formation of Pautrier microabscesses.

In 2009, two years after the initial diagnosis, a new incisional biopsy of the anterior abdomen was performed due to the appearance of new dermatological findings (Figure 1), confirming the diagnosis of mycosis fungoides. Once the diagnosis was confirmed by the second biopsy, the patient began multiple previous treatments with phototherapy (full-body excimer laser, narrowband ultraviolet B, and psoralen plus ultraviolet A), systemic chemotherapy (methotrexate, cyclophosphamide, and gemcitabine), and immunotherapy (interferon and brentuximab vedotin). The patient reported initial improvement in the size of the lesions and pruritus with phototherapy and the immunotherapy interferon. However, subsequently, the skin lesions progressively worsened and were associated with tumor infiltration, neoplastic fever, axillary and inguinal lymph node enlargement, and recurrent skin infections.

Furthermore, in 2018, the patient underwent an allogeneic bone marrow transplant from his brother, with a recommendation and plan for radiotherapy, which was not performed. In the following 2 years, the patient experienced frequent cycles of skin infections and hospitalizations, frequently reporting an increase in lesions and associated symptoms.

In 2021, he underwent a biopsy of a skin lesion on the left thigh and the right inguinal lymph node, given the lymph node involvement, multiple infections, recurrent neoplastic fever, and increase in the extent of the lesions. The immunohistochemical profile showed positivity for CD1a, CD3 (85%), CD20 (15%), CD4 (90%), CD8 (10%), CD2 (60%), CD5 (60%), CD7 (10%), CD30 (50%), and Ki-67 (50%), with ALK1 negative. The skin of the left thigh showed dermal and epidermal proliferation of atypical mononuclear cells, forming a nodule in the dermis. The inguinal lymph node showed partial erasure of the architecture and an immunohistochemical profile consistent with nodal infiltration by T-cell lymphoma. Pathology concluded a diagnosis of folliculotropic mycosis fungoides in transformation to large cell lymphoma.

In 2023, two years after diagnosis of the transformation event, a red bone marrow biopsy was performed, revealing 40% cellularity, demonstrating bone marrow hypoplasia, but without evidence of lymphoma infiltration, even 5 years after the allogeneic bone marrow transplant. In addition, the onset of lesions remained constant, resulting in several hospitalizations and relapses, demonstrating a disease refractory to drug and surgical treatment with bone marrow transplant.

In October 2024, amid bacteremia caused by Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus, the patient presented with diffuse crusted lesions throughout the body, consistent with active mycosis fungoides. He was admitted to the infectious and parasitic diseases unit, and the hematology team advised him to receive palliative and end-of-life care. He developed significant hypoglycemia (15 mg/dL), associated with liver failure, signs of disease progression, and consequently septic shock. He died at age 38, remarkably 17 years after the diagnosis of mycosis fungoides and 3 years after its transformation into large cell lymphoma.

Discussion

Mycosis fungoides is more common in men in their fifth or sixth decade of life [3,9]. However, our patient presented with lesions at the age of 20 years; therefore, it is important to raise the diagnostic hypothesis even in younger patients. Since the patient was diagnosed, underwent the transformation event, and died at least 12 years before the most common age for diagnosis, this case is not only complex, but unique in the comprehension of the disease progression in younger patients and difficulty in diagnosis. Although transformation has already been described in the literature in younger patients [6], significant diagnostic and survival challenges remain. It continues to pose a complex issue for clinical management and is still associated with a poor prognosis.

The initial phase of the disease can present as parapsoriasis, characterized by macular, erythematous, scaly lesions in unexposed areas, which may be pruritic. The disease progresses with plaque-like lesions, followed by tumor-like lesions that may ulcerate. However, atypical cases are increasingly being observed [3], as was the case in the present patient.

In the plaque lesion phase, the superficial dermis presents infiltration with epidermotropism of lymphocytes [9]. Another characteristic finding is the low degree of spongiosis, compared with epidermotropism [3]. In the patient’s first biopsy, atypical lymphocytes and Pautrier microabscesses were identified, both of which were compatible with the diagnosis of mycosis fungoides and were confirmed in an evolutionary manner 2 years later. Mycosis fungoides can transform into large cell lymphoma, and although some authors argue that this transformation is a rare event [1], 20% to 55% of diagnosed patients undergo this transformation [10].

Transformation is marked by the presence of large cells, which represent more than 25% of the infiltrate, each containing a nucleus that is more than 4 times the normal size [1]. Transformation also presents an aggressive evolution [1,10], with resistance to the main treatments [10]. The prognosis varies from 2 to 5 years [1,10], as was observed in the 3-year survival after diagnosis of lymphoma of our patient. It is important to emphasize the difficulty in differentiating transformed mycosis fungoides from primary cutaneous anaplastic large cell lymphoma. In cases of transformed mycosis fungoides, it is estimated that half of the cases present with positive CD30 [1], as was the case in our patient. In this scenario, the differential diagnosis of primary cutaneous anaplastic large cell lymphoma is important, since both can be positive for CD30 [10]. Some studies suggest that CD30 expression is a protective factor in transformed mycosis fungoides, with greater aggressiveness being observed in cases with negative CD30 [1], as noted in this case report, in which the patient survived 1 year past the lower bound of the average post-diagnosis survival.

Therefore, transformation into large cell lymphoma results in a marked worsening of prognosis and should be diagnosed promptly.

Conclusions

We presented a complex case of mycosis fungoides with transformation to large cell lymphoma, highlighting the importance of early diagnosis and rigorous monitoring of patients, especially those with atypical forms and manifestations at younger ages. The clinical evolution and response to treatment in this patient demonstrate the aggressiveness and challenges involved in managing this condition. Therefore, continuous monitoring and biopsies are crucial for early detection of possible transformations and for adapting the therapeutic approach.